HEPATITELE CRONICE Cuprinde boli cu : Manifestari clinice asemanatoare Leziuni necroinflamatorii cronice Evolutie catre ciroza si CHC dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITELE CRONICE Hepatitele cronice virale-B,C Hepatita autoimuna Hepatita cronica indusa de medicamente Boala Wilson dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITELE CRONICE VIRALE B Hepatita cronica cu virus C D Inflamatia persistenta a ficatului cel putin 6 luni dupa expunerea initiala/detectia bolii Sunt diferente importante de virusologie/ epidemiologie/metode de dg/patogeneza intre virusuri dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITA CRONICA CU VIRUS B Hepadnavirus ADN care foloseste pentru replicare ARN- reverstranscriptaza(ca un retrovirus) Asemanari multiple cu virusul HIV (Oncogenit/transmit/integr in genomul gazdei) genomul viral cuprinde - gena S -antigenul de suprafata-HBsAg - gena C-antigen core-HBcAg -gena P- cea mai mare parte din genom- proteina P- ADNpolimeraza/ revers transcriptasa/ RNasa dr cora pop hepatite cronice dr cora pop hepatite cronice

Anvelopa este antigenica(AgHBs) Nucleocapsida este antigenica(AgHBc) Format din ADN dublu catenar inconj de un miez-nucleocapsida inconj de o anvelopa Anvelopa este antigenica(AgHBs) Nucleocapsida este antigenica(AgHBc) Imunitatea la AgHBs este protectoare(natural sau vaccinal) AgHBe deriva din gena de miez dr cora pop hepatite cronice dr cora pop hepatite cronice

dr cora pop hepatite cronice

PATOGENEZA: HBV puternic hepatotrop leziunile apar prin raspunsul imun al gazdei limfocitele T citotoxice- anti HBs -distrug hepatocitele infectate - det clearance viral/hepatita cr un raspuns redus imun al gazdei creste riscul infectiei cronice dr cora pop hepatite cronice dr cora pop hepatite cronice

EPIDEMIOLOGIE prevalenta 300-350 milioane de oameni in lume sunt purtatori Prevalenta crescuta in Africa/Asia Factori de risc -activit sexuala cu risc -droguri iv -dializa -zone cu risc -profesia dr cora pop hepatite cronice dr cora pop hepatite cronice

ANATOMOPATOLOGIE infiltrat inflamator limfocitar portal hepatocite ground-glass (citoplasma vazuta cu H-E- AgHBBs) necroza hepatocitara -piecemeal necrosis inflamatie lobulara si necroza lobulara  AgHBc:Nc hepatocitari/Citoplasma dr cora pop hepatite cronice dr cora pop hepatite cronice

MANIFESTARI CLINICE Boala acuta usoara/asimptomatica Boala cronica* -asimptomatica -manifestari nespec -astenie -artralgii -durere in hip dr -manifest cirozei -manifest cancerului hepatic dr cora pop hepatite cronice dr cora pop hepatite cronice

*HEPATITA CRONICA CU VIRUS B Istoria Naturala risc de cronicizare varsta in mom infectarii 90% NOU NASCUT >50% ADULTI IMUNODEPRIMATI <5% ADULTI IMUNOCOMPETENTI dr cora pop hepatite cronice dr cora pop hepatite cronice

MANIFESTARI CLINICE MANIFESTARI EXTRAHEPATICE -artralgii -glomerulonefrita -poliarterita nodoasa -vasculita -crioglobulinemie dr cora pop hepatite cronice dr cora pop hepatite cronice

EXAMEN CLINIC sarac/normal/manifest cirozei/cancerului +/-Stelute +/-Eritem palmar Ficat Splenomegalie dr cora pop hepatite cronice dr cora pop hepatite cronice

COMPLICATII CIROZA -20% in 5 ani CANCERUL HEPATOCELULAR -creste riscul de 10 ori Relatia HVB-ciroza-cancer dr cora pop hepatite cronice dr cora pop hepatite cronice

DIAGNOSTIC AgHBs AgHBc/AgHBe/PCR TGP/TGO/1-5 ori N, TGP>TGO FA Bilirubina/albumina/timp protrombina N Ecografia biopsia hepatica dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITA CRONICA CU VIRUS B Markeri serologici Stadiul bolii HBsAg Infectie in desfasurare IgM antiHBc Infectie recenta IgG antiHBc/ cu AntiHBs Infectie in antecedente Ac anti HBs vaccinare Ag HBe Replicare virala activa Ac HBe Replicare /infectivitate scazuta AND HVB boala activa/replicare activa *interpretarea testelor serologice in infectia cu virus B dr cora pop hepatite cronice dr cora pop hepatite cronice

EVOLUTIA MARKERILOR SEROLOGICI IN INFECTIA CU VIRUS B dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT Obiectivele tratamentului -preventia complicatiilor pe termen lung -reducerea mortalitatii -ameliorarea simptomatologiei -oprirea replicarii virale/normalizarea TGP -reducerea inflamatiei hepatice -preventia infectarii altor persoane dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT Indicatiile terapiei: · TGP crescut ·        HBV ADN >105 copii/ml dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT INTERFERON -scaderea ADN HVB si disparitia AgHBe la 1/3 din pacienti det scaderea mortalitatii si reducerea complic -interferon pegylat-1/sapt sc/ Alfa Ifn 5 MU/zi -ALT scade -  HBV ADN scade <200pg/ml dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT LAMIVUDINA Oral-ANALOG DE NUCLEOTIDE Inhibitor de revers transcriptaza(prot P) Scaderea viremiei duce la ameliorarea histologiei ADEFOVIR dipivoxil ·        Oral-analog si activ NK cel si IFN ·        Supresia virala determina ameliorarea hist hepatica ·        Nici o rezistenta genotipica la 48 saptamani de terapie ·        Eficace la HBV rezistent la lamivudina dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT TRANSPLANT HEPATIC -tratam pt cei cu boala hep avansata -recurenta dupa transplant frecventa dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITA CRONICA CU VIRUS C VHC virus ARN din familia flavivirusurilor  Replicarea in hepatocit  6 genotipuri 1b europa/ 1a america-corelat cu rasp la tratam/ nu cu evol bolii Peste 50 de subtipuri La acelasi individ variatii in secventa genotipurilor infectante dr cora pop hepatite cronice dr cora pop hepatite cronice

EPIDEMIOLOGIE Prevalenta 1% 170 mil de oameni Variatii geografice-Africa-13% Factori de risc-transfuzii 1990-1992 -droguri iv -hemodializa -profesia -contact sexual<5% Singura infectie hepatitica care are potential de vindecare cu tratam antiviral dr cora pop hepatite cronice dr cora pop hepatite cronice

PATOGENEZA 3 mecanisme patogenice propuse: Direct citopatic Inflam si distructie mediata imun-cel mai probabil LT Autoimunitate mediata viral dr cora pop hepatite cronice dr cora pop hepatite cronice

ANATOMOPATOLOGIE inflam limfocitara periportala hepatita activa cu bridging fibrosis, necroza hepatocitara steatoza agregate limfoide lezarea canalelor biliare ciroza dr cora pop hepatite cronice dr cora pop hepatite cronice

MANIFESTARI CLINICE Particularitati clinice: Infectia acuta este asimptomatica 20%/ rar icter10% Infectie persistenta la peste 80% cazuri- Croniciz dep de-asoc cu HIV/ sex/virsta/inoculare Progresia silentioasa-descoperire intamplatoare Infectia cronica-astenie -depresie -dispepsie -discomfort abd Manifestarile complicatiilor dr cora pop hepatite cronice dr cora pop hepatite cronice

MANIFESTARI CLINICE MANIFESTARI EXTRAHEPATICE Secundare CI formate la contact cu virusul Tiroidita autoimuna Limfom B nonH Diabet Crioglobulinemie Porfirie CT Lichen plan GNMP (rar) dr cora pop hepatite cronice dr cora pop hepatite cronice

COMPLICATII CIROZA CANCER HEPATIC (15% din cei cu ciroza) IH –rar 20-30 ani boala clinica semnificativa dr cora pop hepatite cronice dr cora pop hepatite cronice

DIAGNOSTICUL Teste serologice -detectarea Ac la virus la 2sapt pina la 3 luni de la inf -pt screening -exista 3 generatii de evaluari serologiceRIBA/EIA -ele folosesc antigene recombinate -nu diferentiaza intre acut/ cronic/ vindecare Valoarea TGP-creste la 1luna/ pina la 1000U/L/ fluctueaza-50% N la un mom dat dr cora pop hepatite cronice dr cora pop hepatite cronice

DIAGNOSTICUL ARN viral- PCR –HCV-ARN la 2-3sapt de la infectie -Confirmarea infectiei -inainte de terapie -monitorizarea terapiei Genotiparea Biopsia hepatica-scorul METAVIR dr cora pop hepatite cronice

BIOPSIA HEPATICA dr cora pop hepatite cronice

BIOPSIA HEPATICĂ dr cora pop hepatite cronice

DIAGNOSTIC Test negativ pt Ac anti HCV- exclude infectia Test pozitiv pt Ac anti HCV+ALT crescut- dg pozitiv Test pozitiv pt Ac anti HCV+ALT normal-se face HCV-RNA Imediat dupa expunere HCV-RNA si tratament dr cora pop hepatite cronice

Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917. Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy. Figure 1. Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy. The sequential steps of HCV propagation in a hepatocyte are shown in Panel A. The virus forms complexes with lipoproteins and circulates in the blood. HCV entry factors include scavenger receptor B1 (SCARB1), CD81, claudin 1 (CLDN1), occludin, epidermal growth factor receptor (EGFR), and Niemann-Pick C1-like protein 1 (NPC1L1).4 Panel B shows the virus-encoded gene products displayed topologically on the endoplasmic reticulum membrane, as well as the major viral and host targets that are the focus of agents in advanced clinical development. Other targets in the HCV life cycle, such as viral proteins p7 and NS4B (Panel B), and host targets, including HCV entry factors, lipid metabolism, and membrane signaling pathway involved in replication (Panel A), are also being targeted for HCV therapeutic development. Inhibitors against some of the entry factors have already been developed for other purposes and are currently being tested as treatment for HCV infection. 5– 7 The symbols (+) and (−) refer to the positive and negative strand, respectively, of the viral genome. CypA denotes cyclophilin A, E envelope glycoprotein, GAG glycosaminoglycan, LDLR low-density lipoprotein receptor, NI nucleoside analogue inhibitor, NNI non-nucleoside analogue inhibitor, and NS nonstructural protein. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.

TRATAMENT combinatie IFNα-PEG + RIBAVIRINA IFNα-PEG + RIBAVIRINA+BOCEPREVIR/TELAPREVIR genotipul 1 Ribavirina analog guanozinic Boce/tela inhibitori de proteaze determina un raspuns viral sustinut la 40-80% Raspunsul la terapie: -ALT N si HCV-RNA absent la 6 luni de la oprirea terapiei The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward. dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT RIBAVIRINA Agent antiviral pentru virus ADN/ARN Monoterapia cu RBV:NU ALT seric scazut Ameliorari minore in histologia hepatica Nu modifica HCV-RNA seric Direct inhibition of HCV RNA-dependent RNA polymerase ? dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT Boceprevir -tablete -la 4 sapt de la initierea Ifn+Ribav -ef adverse: oboseala/ anemie/ greata/ cefalee/ insomnie/ neutropenie/ rash/ dermatita exfoliativa/disgeuzie dr cora pop hepatite cronice

Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917. Boceprevir- and Telaprevir-Based Regimens for Treatment of HCV Infection. Figure 2. Boceprevir- and Telaprevir-Based Regimens for Treatment of HCV Infection. The boceprevir-based regimen and the telaprevir-based regimen differ in several aspects: first, with respect to the specific therapeutic regimen for each type of patient (those who have not received prior therapy vs. those who have received prior therapy, including patients with a relapse after an initial response, those with a partial response, and those with no response); second, with respect to the schedule and duration of the combination therapy; and third, with respect to the points at which therapy is changed, depending on the patient's response, and the points at which therapy is stopped. Typically, telaprevir is given together with peginterferon and ribavirin (peginterferon alfa-2a, 180 μg per week, or peginterferon alfa-2b, 1.5 μg per kilogram of body weight per week, in combination with ribavirin, 1000 mg daily for a patient with a body weight of less than or equal to 75 kg and 1200 mg daily for a patient with a body weight of >75 kg) during the first 12 weeks of therapy; peginterferon and ribavirin are then continued without the protease inhibitor for a total of either 24 or 48 weeks, depending on the virologic response to the triple therapy (response-guided therapy). In contrast, boceprevir is administered starting 4 weeks after the initiation of peginterferon and ribavirin (at the same doses as above) and is continued for a total of 28 or 48 weeks, again depending on the virologic response. In general, with both regimens, patients with cirrhosis should receive the same treatment as patients who have not had a response to previous therapy. The stopping rules were as follows: for the telaprevir-based regimen, patients with an HCV RNA level greater than 1000 IU/ml at week 4 or week 12 should discontinue all three drugs; for the boceprevir-based regimen, patients with an HCV RNA level greater than or equal to 100 IU/ml at week 12 should discontinue all three drugs. For both regimens, patients with detectable HCV RNA at week 24 should discontinue therapy. Boc denotes boceprevir, PIFN peginterferon alfa, R ribavirin, and Tpv telaprevir. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.

TRATAMENT sofosbuvir (400 mg) si RBV plus PEG 12 sapt HCV genotip 1 sofosbuvir (400 mg) plus simeprevir (150 mg), +/- RBV 12 sapt fără IFN dr cora pop hepatite cronice

TRATAMENT TRANSPLANT HEPATIC - indicaţia cea mai frecventă recidiva este universală Imunoprofilaxia-nu Retratament Genotype 3 responses less well than genotype 2 RVR important predictor of SVR Consider shorter duration Rx (e.g. 16 wks) only if RVR and other favorable baseline factors Consider longer duration Rx (>24 weeks) and weight-based ribavirin if no RVR Effect of partial versus complete EVR not assessed, but effect likely to be similar to G1 patients If no RVR and no complete EVR, consider longer Rx (48 weeks) and higher ribavirin doses dr cora pop hepatite cronice dr cora pop hepatite cronice

COMPLICAŢIILE TERAPIEI IFN - Simptome gripale - Oboseală - Agravarea starii generale - Supresie medulară  RIBAVIRINĂ                    - Anemie hemolitica -boala coronariană/art. periferica - Insuficienţa cardiacă Long-term virological response after SVR: 98-99% Clinical relevance of detection of small amounts of HCV RNA uncertain Fibrosis progression rate: slowed Especially responders, including reversal of cirrhosis Incidence of HCC: reduced Especially patients with SVR Life expectancy and survival: improved Decreased risk of liver-related death dr cora pop hepatite cronice dr cora pop hepatite cronice

COMPLICAŢIILE TERAPIEI CI terapiei cu IFN + RIBAVIRINA Boli psihice prost controlate Sarcina Ciroza decompensată Insuficienţa renala Pancreatită dr cora pop hepatite cronice dr cora pop hepatite cronice

COMPLICAŢIILE TERAPIEI CI relative ale terapiei cu IFN+RIBAVIRINA o       Boli CV o       DZ o       Convulsii o       Boli pulmonare o       L<1500/mm o       Trombocite<75000/mm o       Varsta>65 ani dr cora pop hepatite cronice dr cora pop hepatite cronice

HEPATITA CRONICA CU VIRUS D Molecula ARN unicatenara AgHBs este folos ca proteina de anvelopa HDV se reactiveaza in prezenta HBV HDV infecteaza numai hepatocitele dr cora pop hepatite cronice dr cora pop hepatite cronice

EPIDEMIOLOGIE: numai in prezenta HBV: ·        coinfectie-ambele virusuri simultan ·        suprainfectia la o HBV cronica 15.000.000 persoane infectate droguri iv f de risc cel mai important dr cora pop hepatite cronice dr cora pop hepatite cronice

MANIFESTARI CLINICE simptome nespecifice infectia trebuie suspectata: ·        infectie HBV fulminanta ·        infectie HBV acuta care se amelioreaza dar recidiveaza ulterior ·        coinfectia HBV-HDV: boala acuta mai severa decat HBV singura risc crescut de IHF dr cora pop hepatite cronice dr cora pop hepatite cronice

TRATAMENT Alfa Ifn raspuns la 50% Raspuns viral/biochimic rar sustinut 9MU de 3 ori/saptaman Lamivudina si AF-? Transplant hepatic dr cora pop hepatite cronice dr cora pop hepatite cronice